CN107586300A - Novel crystal forms II, its preparation method and its application of oxolinic acid - Google Patents
Novel crystal forms II, its preparation method and its application of oxolinic acid Download PDFInfo
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Abstract
This invention She is Ji the crystal formation II of oxolinic acid, it is in the X-ray powder diffraction figure for the use of radiation source being Cu K α, it is to have characteristic absorption peak at 10.22 °, 16.68 °, 18.55 °, 19.73 °, 20.62 °, 24.75 °, 27.28 ° and 31.04 ° in the θ of the angle of diffraction 2,2 θ error range is ± 0.2 °.The present invention also provides Suo Shu oxolinic acid crystal formations II preparation method and applications.The crystal formation II of this invention Suo Shu oxolinic acids has the advantages that purity is high, stability is good.
Description
Technical field
This invention She Ji the novel crystal forms II of oxolinic acid (1- ethyl -6,7- methylene-dioxy -4- quinolone -3- carboxylic acids), its
Preparation method and applications.
Background technology
A kind of different solid forms of active constituents of medicine can have different characteristics, and can provide some advantages,
Such as in terms of stability, dissolubility or bioavilability.The storage for being found to be bulk drug of new solid form improves work
The characteristic of the pharmaceutical dosage form of property composition provides possibility.
Oxolinic acid (Oxolinic Acid, abbreviation OA), alias Oxolinic Acid, 1- ethyl -6,7- methylene-dioxy -4- quinolines
Promise ketone -3- carboxylic acids, No. CAS:14698-29-4, its structural formula are：
Oxolinic acid belongs to carbostyril family antibacterial drugs, particularly has very strong antibacterial to live to Gram-negative bacteria and mycoplasma
Property, it has also become prevent and treat the main antibacterials of fish diseases.
WO201230284 A1 disclose the preparation method of Yi pot method He Cheng oxolinic acids.The patent does not carry out detailed to crystal formation
Thin research.
Oxolinic acid (article No.s can be commercially available from Sigma companies at present：O0877-25G it is) that a kind of crystal formation is (herein
It is named as crystal formation I), but oxolinic acid crystal formation I purity is less than 99%, less stable.
The content of the invention
Therefore, the technical problems to be solved by the invention are in overcoming the purity for now having oxolinic acid crystal formation I in skill art low, steady
The defects of qualitative poor, there is provided the novel crystal forms II of Yi Zhong oxolinic acids.The novel crystal forms II of this invention oxolinic acids is compared to prior art
Oxolinic acid crystal formation I, have the advantages that higher purity and more preferable stability, more conform to the quality requirement of medicine production,
It is easy to preserve for a long time, can be applied to the production of medicine, the preparation of standard items etc..
One object of the present invention is to provide Yi Zhong oxolinic acid crystal formations II.Suo Shu oxolinic acid crystal formation II are being using radiation source
It is to have characteristic absorption peak, 2 θ error model at 10.22 ° and 27.28 ° in the θ of the angle of diffraction 2 in Cu-K α X-ray powder diffraction figure
Enclose for ± 0.2 °.In one embodiment, the crystal formation II of Qian Shu oxolinic acids characteristic absorption diffraction maximum relative intensity is more than
90%.
, Suo Shu oxolinic acid crystal formation II are using the X-ray powder diffraction figure that radiation source is Cu-K α in one embodiment
In, it is to have characteristic absorption peak at 10.22 °, 24.75 ° and 27.28 ° in the θ of the angle of diffraction 2,2 θ error range is ± 0.2 °.One
In embodiment, the crystal formation II of Qian Shu oxolinic acids characteristic absorption diffraction maximum relative intensity is more than 40%.
, Suo Shu oxolinic acid crystal formation II are using the X-ray powder diffraction figure that radiation source is Cu-K α in one embodiment
In, it is to have spy at 10.22 °, 16.68 °, 18.55 °, 19.73 °, 20.62 °, 24.75 °, 27.28 ° and 31.04 ° in the θ of the angle of diffraction 2
Absworption peak is levied, 2 θ error range is ± 0.2 °.In one embodiment, Qian Shu oxolinic acid crystal formations II characteristic absorption diffraction
Peak relative intensity is more than 10%.
, Suo Shu oxolinic acid crystal formation II are using the X-ray powder diffraction figure that radiation source is Cu-K α in one embodiment
In, the θ of the angle of diffraction 2 be 10.22 °, 11.92 °, 12.26 °, 16.68 °, 18.55 °, 19.73 °, 20.62 °, 21.92 °,
There are characteristic absorption peak, 2 θ mistake at 24.10 °, 24.75 °, 26.19 °, 26.43 °, 27.28 °, 28.38 °, 31.04 ° and 33.09 °
Poor scope is ± 0.2 °.In one embodiment, Qian Shu oxolinic acid crystal formations II characteristic absorption diffraction maximum relative intensity is more than
5%.
, Suo Shu oxolinic acid crystal formation II are using the X-ray powder diffraction figure that radiation source is Cu-K α in one embodiment
In, the θ of the angle of diffraction 2 be 10.22 °, 11.92 °, 12.26 °, 16.68 °, 18.55 °, 19.73 °, 20.62 °, 21.92 °, 23.60,
There is characteristic absorption at 24.10 °, 24.75 °, 26.19 °, 26.43 °, 27.28 °, 28.38 °, 31.04 °, 33.09 ° and 33.86 °
Peak, 2 θ error range is ± 0.2 °.In one embodiment, Qian Shu oxolinic acid crystal formations II characteristic absorption diffraction maximum is relative
Intensity is more than 2%.
In one embodiment, Suo Shu oxolinic acid crystal formations II has X-ray powder diffraction figure as shown in Figure 1.
In one embodiment, Suo Shu oxolinic acid crystal formation II in differential scanning calorimetric analysis (DSC) collection of illustrative plates about
There is feature endothermic peak between 319-321 DEG C.
In one embodiment, Suo Shu oxolinic acid crystal formation II in differential scanning calorimetric analysis (DSC) collection of illustrative plates
320.71 DEG C there is feature endothermic peak.
It is a further object to provide a kind of method for preparing Suo Shu oxolinic acid crystal formations II, the preparation method
Comprise the following steps：
(1) oxolinic acid heating is dissolved in solvent orange 2 A, wherein the solvent orange 2 A is aqueous slkali；
(2) solvent B is added, cooling, crystal separates out, wherein the solvent B is polar organic solvent.
In one embodiment, the solvent orange 2 A is selected from following aqueous slkali：Ammoniacal liquor, potassium hydroxide aqueous solution, hydroxide
Sodium water solution or its mixture.
In one embodiment, the solvent B is one or more polar organic solvents in following：Methanol,
Ethanol, normal propyl alcohol and isopropanol.
In one embodiment, the concentration of the aqueous slkali is 0.1-0.5mol/L.Preferably, the concentration of the aqueous slkali
It is more preferably 0.4-0.5mol/L for 0.2-0.5mol/L, preferably 0.3-0.5mol/L, more preferably 0.3-0.4mol/L,
Most preferably 0.4mol/L.
In one embodiment, solvent orange 2 A and solvent B volume ratio are 1:10-1:50.Preferably, solvent orange 2 A and solvent B
Volume ratio is 1：20-1：50, preferably 1：30-1：50, it is more preferably 1：40-1：50, most preferably 1：40.
The mass volume ratio of , oxolinic acids and solvent orange 2 A is 20-120mg/mL in one embodiment.Preferably , oxolinic acids with
The mass volume ratio of solvent orange 2 A be 20-110mg/mL, 20-100mg/mL, 20-90mg/mL, 20-80mg/mL, 20-70mg/mL,
20-60mg/mL, 20-50mg/mL, 20-40mg/mL or 20-30mg/mL, it is more preferably 20-50mg/mL, most preferably 40-
50mg/mL。
In one embodiment, the temperature of the heating of the step (1) is 20-60 DEG C.Preferably, the temperature of the heating
It is more preferably 30-50 DEG C for 30-60 DEG C, most preferably 40-50 DEG C.
In a preferred embodiment, in the step (2), it is additionally included in after adding solvent B, is placed in 2-10 DEG C of environment
Lower standing.
In one embodiment, the step of methods described also includes filtering and drying obtained oxolinic acids crystal formation II.
In one embodiment, in filter process, crystal is washed using alcohol reagent.In one embodiment, it is described
Alcohol reagent includes but is not limited to methanol, ethanol or normal propyl alcohol.
Organic impurities can effectively be controlled using alcohol reagent washing crystal, improve the purity of sample.
In a typical embodiment, Bei oxolinic acids crystal formation II processed of the present invention method comprises the following steps：
(1) oxolinic acid is dissolved in solvent orange 2 A by , at a temperature of 20-60 DEG C, preferably stirs 5-10min；
(2) solvent B is added, 10-30min is preferably stirred, is placed under 2-10 DEG C of environment and stands 24-48h, crystal separates out；
(3) filtration drying, you can get oxolinic acid crystal formation medicines II.
In one embodiment, the solvent orange 2 A is selected from following aqueous slkali：Ammoniacal liquor, potassium hydroxide aqueous solution, hydroxide
Sodium water solution or its mixture.
In one embodiment, the solvent B is one or more polar organic solvents in following：Methanol,
Ethanol, normal propyl alcohol and isopropanol.
In one embodiment, the concentration of the aqueous slkali is 0.1-0.5mol/L.Preferably, the concentration of the aqueous slkali
0.2-0.5mol/L, preferably 0.3-0.5mol/L, it is more preferably 0.4-0.5mol/L, more preferably 0.3-0.4mol/L, most
Preferably 0.4mol/L.
In one embodiment, solvent orange 2 A and solvent B volume ratio are 1:10-1:50.Preferably, solvent orange 2 A and solvent B
Volume ratio is 1：20-1：50, preferably 1：30-1：50, it is more preferably 1：40-1：50, most preferably 1：40.
The mass volume ratio of , oxolinic acids and solvent orange 2 A is 20-120mg/mL in one embodiment.Preferably , oxolinic acids with
The mass volume ratio of solvent orange 2 A be 20-110mg/mL, 20-100mg/mL, 20-90mg/mL, 20-80mg/mL, 20-70mg/mL,
20-60mg/mL, 20-50mg/mL, 20-40mg/mL or 20-30mg/mL, it is more preferably 20-50mg/mL, most preferably 40-
50mg/mL。
In one embodiment, in filter process, crystal is washed using alcohol reagent.In one embodiment, it is described
Alcohol reagent includes but is not limited to methanol, ethanol or normal propyl alcohol.
In the present invention, foregoing filtration and drying are this area routine operation.
The present invention also provides Suo Shu oxolinic acid crystal formation II and caused in preparation for preventing and/or treating Gram-negative bacteria
Poultry, fowl and aquatic animal infectious disease medicine in application.
The poultry, fowl and aquatic animal infectious disease include but is not limited to go out salmon aeromonas, Aeromonas hydrophila, eel arc
The disease of the infection such as bacterium.
On the basis of common sense in the field is met, above-mentioned each preferred embodiment, can be combined, obtain the present invention respectively compared with
Good embodiment.
Compared with the crystal formation I of prior art, above method get oxolinic acid crystal formations II of the present invention has more than 99%
Chromatographic purity, crystallinity are high.
The crystal formation II of Yi Zhong oxolinic acids provided by the invention preparation method has that reproducible, easy to operate, product is pure
The advantages that degree is high, stability is good.
Brief description of the drawings
Fig. 1 is this invention oxolinic acid crystal formations II X-ray powder diffraction (XRPD) figure.
Fig. 2 is this invention oxolinic acid crystal formations II differential scanning calorimetric analysis (DSC) figure.The feature in the DSC collection of illustrative plates
Endothermic peak is between about 319-321 DEG C.It is highly preferred that feature endothermic peak is at 320.71 DEG C in the DSC collection of illustrative plates.
Fig. 3 is this invention oxolinic acid crystal formations II HPLC collection of illustrative plates.
Fig. 4 is Xian You Ji Shu oxolinic acid crystal formations I XRPD collection of illustrative plates.
Fig. 5 is Xian You Ji Shu oxolinic acid crystal formations I X-ray powder diffraction differential scanning calorimetric analysis (DSC) figure.
Fig. 6 is Xian You Ji Shu oxolinic acid crystal formations I HPLC collection of illustrative plates.
Embodiment
Following instance explains the present invention in more detail.Institute's temperature displaying function is Celsius temperature.If without other statement, room temperature be 18 to
25 DEG C of scope and shown percentage is by weight.
In the present invention, involved X-ray powder diffraction (XRPD) tester is：Bruker D8Advance diffraction
Instrument；Test condition：Use Cu targets wavelength forK α X-rays, 40kV/40mA；Scanned from 3.000 degree to 44.993
Degree, continuous scanning, scanning step are 0.020 degree, sweep speed：8 degree/min.Detect environmental condition：21 DEG C of temperature, humidity
50%.
In the present invention, involved differential scanning calorimetric analysis (DSC) instrument is：Perkin Elmer Diamond DSC
Power compensation differential scanning calorimeter；Test condition：Aluminium dish, blow-by, scanning range are 55 DEG C~400 DEG C, heating rate
For 10 DEG C/min, 55 DEG C of holding 1min, atmosphere is nitrogen.Detect environmental condition：20 DEG C of temperature, humidity 56%.
In the present invention, the instrument of involved liquid chromatogram (HPLC) analysis is Hewlett-Packard's HP1100 liquid chromatographs：
Test condition：
A. mobile phase：A phases：PH=2.4 phosphoric acid-triethylamine buffer solution (takes phosphoric acid 3.4mL, dissolved with water and dilute
Release to 1000mL, with triethylamine pH value to 2.4)；B phases：Acetonitrile；A phases：B phase=75:25.
B. chromatographic column and detector：ODS-C18 (5 μm, 4.6*250mm), column temperature：35℃；Detector is UV-detector,
Detection wavelength：254nm.
Detect environmental condition：19 DEG C of temperature, humidity 60%.
Cai oxolinic acids are purchased from Sigma Gong Si oxolinic acid product (article No.s for foregoing in following embodiment：
O0877-25G), remaining each reagent of use is commercially commercially available.
Embodiment 1
Oxolinic acid crystal formation II preparation
0.5g oxolinic acids are dissolved in 10mL 0.4mol/L sodium hydroxide solutions, 45 DEG C of stirring 20min, add 100mL first
Alcohol, 30min is stirred, 48h is stood under 4 DEG C of environment, filtered, be dried to obtain colourless rhabdolith, purity 99.19%, through XRPD
Jian Ce Wei oxolinic acid crystal formation II, are clear crystal.
Embodiment 2
Oxolinic acid crystal formation II preparation
0.2g oxolinic acids are dissolved in 10mL 0.3mol/L ammonia spirits, 35 DEG C of stirring 20min, 100mL ethanol is added, stirs
20min is mixed, 24h is stood under 4 DEG C of environment, is filtered, is dried to obtain colourless rhabdolith, purity 99.16%, is detected as through XRPD
Oxolinic acid crystal formation II, it is clear crystal.
Embodiment 3
Oxolinic acid crystal formation II preparation
0.8g oxolinic acids are dissolved in 10mL 0.5mol/L sodium hydroxide solutions, 45 DEG C of stirring 30min, add 200mL positive third
Alcohol, 30min is stirred, 24h is stood under 4 DEG C of environment, filtered, be dried to obtain colourless rhabdolith, purity 99.15%, through XRPD
Jian Ce Wei oxolinic acid crystal formation II, are clear crystal.
Embodiment 4
0.4g oxolinic acids are dissolved in 10mL 0.5mol/L potassium hydroxide solutions, 30 DEG C of stirring 20min, add 120mL first
Alcohol, 10min is stirred, 48h is stood under 10 DEG C of environment, filtered, be dried to obtain colourless rhabdolith, purity 99.14%, through XRPD
Jian Ce Wei oxolinic acid crystal formation II, are clear crystal.
Embodiment 5
1.2g oxolinic acids are dissolved in 10mL 0.5mol/L potassium hydroxide solutions, 60 DEG C of stirring 20min, add 500mL second
Alcohol, 30min is stirred, 48h is stood under 10 DEG C of environment, filtered, be dried to obtain colourless rhabdolith, purity 99.14%, through XRPD
Jian Ce Wei oxolinic acid crystal formation II, are clear crystal.
Embodiment 6
0.4g oxolinic acids are dissolved in 10mL 0.5mol/L ammonia spirits, 35 DEG C of stirring 20min, 300mL methanol is added, stirs
30min is mixed, 48h is stood under 4 DEG C of environment, is filtered, is dried to obtain colourless rhabdolith, purity 99.14%, is detected as through XRPD
Oxolinic acid crystal formation II, it is clear crystal.
The measure of the oxolinic acid crystal formation II characters of 7 the embodiment of the present application of embodiment 1
1st, oxolinic acid crystal formation II X-ray powder diffraction
It is measured using foregoing instrument, assay method and operating condition, parameter.
Oxolinic acid crystal formation II X-ray powder diffraction pattern is as shown in figure 1, specific data therein are as shown in table 1：
The Fig. 1 of table 1 X-ray powder diffraction related data
2nd, the oxolinic acid crystal formations II of the embodiment of the present application 1 differential scanning calorimetric analysis (DSC)
It is measured using foregoing instrument, assay method and operating condition, parameter.
Oxolinic acid crystal formation II differential scanning calorimetric thermogram spectrum is as shown in Figure 2.Feature endothermic peak exists in the DSC collection of illustrative plates
Between about 319-321 DEG C.
In the DSC collection of illustrative plates, the oxolinic acid crystal formations II of the embodiment of the present application 1 feature：Oxolinic acid crystal formation II is 320.71
There is 1 fusing endothermic peak at DEG C.
The oxolinic acid crystal formation II Yu Xian You Ji Shu oxolinic acid crystal formations I of 8 the embodiment of the present application of embodiment 1 comparison
Carried out using foregoing instrument, assay method and operating condition, parameter Dui Xian You Ji Shu oxolinic acid crystal formations I
XRPD, DSC and HPLC are detected, and its testing result difference is as Figure 4-Figure 6.Wherein, Xian You Ji Shu oxolinic acid crystal formations I differential is swept
Thermometric analysis (DSC) collection of illustrative plates (Fig. 5) display is retouched, feature endothermic peak has 1 fusing to inhale at about 322.62 DEG C in its DSC collection of illustrative plates
Thermal spike.
The oxolinic acid crystal formations II of the embodiment of the present application 1 purity data and XRPD figures and prior art is shown in table 2
Comparison between oxolinic acid crystal formations I purity data and XRPD figures.
Table 2
Xian You Ji Shu oxolinic acid crystal formations I X-ray powder diffraction pattern is as shown in figure 4, specific data such as table 3 therein
It is shown：
The Fig. 4 of table 3 Xian You Ji Shu oxolinic acid crystal formations I X-ray powder diffraction related data
From the data of above-mentioned table 2 and table 3, oxolinic acid crystal formation II of the present invention is different from the crystal formation I of prior art
Crystal formation, and there is higher purity compared to the crystal formation I of prior art.
The stability of embodiment 9 compares
In the present embodiment, the oxolinic acid crystal formation II Yu Xian You Ji Shu oxolinic acid crystal formations I of the embodiment of the present application 1 is distinguished
Carry out stability test (experimental method referring to《Chinese veterinary pharmacopoeia》The stability testing method that 2010 editions annex are recorded), and
Result is contrasted.
Dui Xian You Ji Shu oxolinic acid crystal formation I prepare oxolinic acid crystal formations II with the embodiment of the present application 1 and carry out hot test
The comparative study of (40 DEG C and 60 DEG C).As a result as shown in table 4 and table 5.
The oxolinic acid crystal formation II of 4 the embodiment of the present application of table 1 and the crystal formation I of prior art are in 40 DEG C of comparative test results of high temperature
The oxolinic acid crystal formation II of 5 the embodiment of the present application of table 1 and the crystal formation I of prior art are in 60 DEG C of comparative test results of high temperature
From above-mentioned data, the oxolinic acid crystal formation II of the embodiment of the present application 1 have excellent compared to the crystal formation I of prior art
Different stability.The oxolinic acid crystal formations II of the embodiment of the present application 1 purity reaches more than 99%, more conforms to the matter of medicine production
Amount requires, and is easy to preserve for a long time.
The present invention is not limited by shown above and description embodiment, but can be changed within the scope of the claims
Become.
Claims (10)
1. oxolinic acid crystal formation II, it is characterised in that the crystal formation II is using the X-ray powder diffraction figure that radiation source is Cu-K α
In, it is to have spy at 10.22 °, 16.68 °, 18.55 °, 19.73 °, 20.62 °, 24.75 °, 27.28 ° and 31.04 ° in the θ of the angle of diffraction 2
Absworption peak is levied, 2 θ error range is ± 0.2 °.
2. such as claim 1 Suo Shu oxolinic acid crystal formation II, wherein, the crystal formation II has X-ray powder as shown in Figure 1
Diffraction pattern.
3. such as claim 1 Suo Shu oxolinic acid crystal formation II, wherein, the crystal formation II in differential scanning calorimetric thermogram
320.71 DEG C there is feature endothermic peak.
A kind of 4. method for preparing the oxolinic acids crystal formation II as any one of claim 1-3, it is characterised in that the system
Preparation Method comprises the following steps：
(1) oxolinic acid heating is dissolved in solvent orange 2 A, wherein the solvent orange 2 A is aqueous slkali；
(2) solvent B is added, cooling, crystal separates out, wherein the solvent B is polar organic solvent.
5. Bei oxolinic acids crystal formation II processed as claimed in claim 4 method, wherein, the solvent orange 2 A is selected from following alkali soluble
Liquid：Ammoniacal liquor, potassium hydroxide aqueous solution, sodium hydrate aqueous solution or its mixture, and the solvent B be in following one
Kind or a variety of polar organic solvents：Methanol, ethanol, normal propyl alcohol and isopropanol.
6. the method for the Bei oxolinic acids crystal formation II processed as described in claim 4 or 5, wherein, the concentration of the aqueous slkali is 0.1-
0.5mol/L。
7. the method for the Bei oxolinic acids crystal formation II processed as described in claim 4 or 5, wherein, solvent orange 2 A and solvent B volume ratio are
1:10-1:50；He the mass volume ratio of/Huo oxolinic acids and solvent orange 2 A is 20-120mg/mL.
8. the method for the Bei oxolinic acids crystal formation II processed as described in claim 4 or 5, wherein, the temperature of the heating of the step (1)
For 20-60 DEG C.
9. the method for the Bei oxolinic acids crystal formation II processed as described in claim 4 or 5, it also includes filtering and dries obtained Evil
The step of quinoline acid crystals type II.
10. oxolinic acids crystal formation II is being prepared for preventing and/or treating gram-negative as any one of claim 1-3
Property it is microbial poultry, fowl and aquatic animal infectious disease medicine in application.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5077525A (en) * | 1973-11-21 | 1975-06-24 | ||
| EP0300107A1 (en) * | 1986-02-19 | 1989-01-25 | Vetoquinol S.A. | Ester, thioester and amide derivatives of oxolinic acid, process for their synthesis and their therapeutical use |
| EP0549263A2 (en) * | 1991-12-27 | 1993-06-30 | Chemagis Ltd. | A process for the preparation of N-alkyl-3,4-dialkyloxyanilines and derivatives thereof |
| JPH06157538A (en) * | 1992-11-30 | 1994-06-03 | Sumitomo Chem Co Ltd | Purification of quinolonecarboxylic acid |
| JPH07145170A (en) * | 1993-11-22 | 1995-06-06 | Sumitomo Chem Co Ltd | Production of quinolonecarboxylic acids |
| WO2015198349A1 (en) * | 2014-06-25 | 2015-12-30 | Council Of Scientific & Industrial Research | A one pot synthesis of 3-substituted quinoline carboxylates and its derivatives |
-
2016
- 2016-07-08 CN CN201610536915.3A patent/CN107586300A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5077525A (en) * | 1973-11-21 | 1975-06-24 | ||
| EP0300107A1 (en) * | 1986-02-19 | 1989-01-25 | Vetoquinol S.A. | Ester, thioester and amide derivatives of oxolinic acid, process for their synthesis and their therapeutical use |
| EP0549263A2 (en) * | 1991-12-27 | 1993-06-30 | Chemagis Ltd. | A process for the preparation of N-alkyl-3,4-dialkyloxyanilines and derivatives thereof |
| JPH06157538A (en) * | 1992-11-30 | 1994-06-03 | Sumitomo Chem Co Ltd | Purification of quinolonecarboxylic acid |
| JPH07145170A (en) * | 1993-11-22 | 1995-06-06 | Sumitomo Chem Co Ltd | Production of quinolonecarboxylic acids |
| WO2015198349A1 (en) * | 2014-06-25 | 2015-12-30 | Council Of Scientific & Industrial Research | A one pot synthesis of 3-substituted quinoline carboxylates and its derivatives |
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| Title |
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| 吕扬 等: "《晶型药物》", 31 October 2009, 人民卫生出版社 * |
| 祝宏 等: ""噁喹酸的合成工艺研究"", 《化学工程与装备》 * |
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